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Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah.

The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the alpha-ketoglutarate dehydrogenase complex) is a rate-limiting enzyme in the mitochondrial Krebs cycle. Here we report that the RING finger ubiquitin-protein isopeptide ligase Siah2 binds to and targets OGDHC-E2 for ubiquitination-dependent degradation. OGDHC-E2 expression and activity are elevated in Siah2(-/-) cells compared with Siah2(+)(/)(+) cells. Deletion of the mitochondrial targeting sequence of OGDHC-E2 results in its cytoplasmic localization and rapid proteasome-dependent degradation in Siah2(+)(/)(+) but not in Siah2(-/-) cells. Significantly, because of its overexpression or disruption of the mitochondrial membrane potential, the release of OGDHC-E2 from mitochondria to the cytoplasm also results in its concomitant degradation. The role of the Siah family of ligases in the regulation of OGDHC-E2 stability is expected to take place under pathological conditions in which the levels of OGDHC-E2 are altered.

Pubmed ID: 15466852

Authors

  • Habelhah H
  • Laine A
  • Erdjument-Bromage H
  • Tempst P
  • Gershwin ME
  • Bowtell DD
  • Ronai Z

Journal

The Journal of biological chemistry

Publication Data

December 17, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA78419

Mesh Terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cytoplasm
  • Electrophoresis, Polyacrylamide Gel
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Ketoglutarate Dehydrogenase Complex
  • Kinetics
  • Membrane Potentials
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria
  • Nuclear Proteins
  • Plasmids
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Structure, Tertiary
  • Transcription Factors
  • Transfection
  • Transgenes
  • Ubiquitin
  • Ubiquitin-Protein Ligases